The immunologic interplay of the intact spleen with other lymphoid organs during the rejection or acceptance of organ allografts or the induction of graft-versus-host disease (GVHD) is not yet fully understood. Preliminary studies have shown that vascularized whole-organ spleen allografts exchanged between inbred strains of rats and guinea pigs, incompatible at the major histocompatibility complex (MHC), survived indefinitely or induced lethal GVHD in the absence of immunosuppression in immunocompetent hosts. Single spleen cell suspensions were ineffective. Rats with accepted spleen allografts were rendered specifically unresponsive for other organ grafts of the spleen donor strain. The underlying mechanisms of these phenomena are still unknown and will be the subject of the proposed research. The identification and analysis of cellular and humoral events in spleen grafted animals will contribute to a fuller understanding of immunologic unresponsiveness and lethal GVHD. The use of inbred animals, recombinant at the MHC, will help to identify the influence of the A and B-region (rat) and of the B and I-region (guinea pig) on immunologic unresponsiveness and lethal GVHD in this model. The information gained will also provide an insight into the immunologic modulation of host responses by spleen grafts.